C-norpregnanes



United States Patent 3,325,536 C-NORPREGNANES Kenneth G. Holden,Stratford, N.J., and James F. Kerwin, Broomall, Pa., assignors to SmithKline & French Laboratories, Philadelphia, Pa., a corporation ofPennsylvania No Drawing. Filed Mar. 19, 1965, Ser. No. 441,315

8 Claims. (Cl. 260-488) t This invention relates to steroid compoundshaving physiological activity. In particular, the invention relates toC-norpregnanes having central nervous system depressant activity andhormonal activity, and to intermediates for the preparation thereof. Thecompounds are primarily p'rogestational and antiandrogenic agents.

The compounds of the present invention are characterized by a steroidalpregnane nucleus in which the C-ring possesses carbon atoms rather thanthe usual 6 carbon atoms, and is thus designated a C-norpregnane. Theyare further characterized byeither a ketone or alcohol group at the 3and 20-positions, an optional double bond at the 4-5 positions, and anoptional hydroxy or lower acyloxy group at the 17tl-POSltlOH. They thusmay be represented by the following structural formula:

I wherein:

A represents a single or a double bond; R is hydrogen, hydroxy, or loweracyloxy; and Xis =0 or =(H, OH).

Patented June 13, 1967 For purposes of this invention the term loweracyloxy is intended to represent an acyl group having up to 5 carbonatoms therein. Particularly intended are such groups as acetyl,propionyl, 'butyryl, and isobutyryl.

Also included within the scope of the invention are the C-norpregnaneshaving an ll-keto or hydroxy group, and a 4-bromo compound, all of whichcompounds are intermediates useful for the preparation of thephysiologically active C-norpregnanes of the present invention.

The C-norpregnane compounds are prepared as described below by a seriesof reactions which may be readily understood with the aid of Chart I. A,2Qt3-dihYdTOXY-SB-PICgHaII-IZ'OIIG (II) is oxidized with gaseous oxygenin the presence of a strong base such as potassium tert-butoxide. Whenthe reaction is maintained at room temperature for two hours and thenworked up, the enol form (III) of an 11,12-diketopregnaneis obtained.When the reaction is maintained at room temperature for about 24 hours,and then refluxed for an equal length of time, an oxidation to III and abenzylic acid-type rearrangement to the C-nor hydroxy acid IV bothoccur. The keto enol III itself may be converted to the C-nor hydroxyacid IV by refluxing overnight with a strong base like potassiumtert-butoxide in butanol. Oxidation with lead tetraacetate in aceticacid results in the formation of the C-nor-1l-ketopregnane-3,20-diol(V). The ll-keto group is reduced by means of a metal such as sodiumwith anhydrous hydrazine in an anhydrous alcohol such as propyleneglycol. The product, Sfi-C-norpregnane-3 ,2013-diol, is separated fromthe ll-hydroxy by-product by fractional crystallization. The diol isthen oxidized with chromic acid to 5,8-C-norpregnane-3,20- dione (VI).This compound is an important intermediate for the preparation of the Aanalog and the 17- oxygenated derivatives of both the A and thesaturated compounds. It also possesses antiandrogenic and centralnervous system depressant activities.

CHART I CH: (1H3 (llfia 0 CI-IOH CHOH if (BHOH [l COOH HO-- HO-- HO- H HH II III IV CH3 (3H3 (EH3 |3= CHOH 1 O 2 steps e----- 0 O.- HO-- 2 H HBr VII VI V l 12 steps on; (1H3 :0 0 OAc i ll ACO

VIII IX m3 CH: =0 :0 j' -orr --OAo i i o o:

XIII XII Introduction of the 4-5 double bond is accomplished bybromination at the 4-position in the presence of an acid catalyst suchas p-toluenesulfonic acid. Dehydrobromination is accomplished bytreatment of the bromo compound VII with semicarbazide, followed byaddition of pyruvic acid in aqueous acetic acid. The resulting product,C-norpregn4-ene-3,20-dione (VIII, C-norprogesterone), is active as aprogestational agent.

The Hot-oxygenated group is introduced by the following series ofreactions. The C-norpregnane-3,20-dione V1 is reduced to the3a-hydroxy-20-one with a limited amount of sodium borohydride. Thisintermediate, upon treatment with p-toluenesulfonic acid in aceticanhydride, is converted to the enoil acetate IX. Treatment of thiscompound with a peracid such as m-chloroperbenzoic acid results in theformation of 3a,2018-diacetoxy-l70,20aepoxy -5/3- C-norpregnane (X).Basic hydrolysis with sodium hydroxide solution yields3a,17u-dihydroxy-5 8-C- norpregnamZO-one (XI). The diol can bediacylated with a reagent such as acetic anhydride, selectivelyhydrolyzed at the 3-position with one equivalent of a base such assodium hydroxide, and then oxidized to a 3-ketone with chromic acid. Theproduct is the intermediate 17u acetoxy-Sfi-C-norpregnane-3,20-dione.This compound is brominated and then dehydrobrominated to give theprogestational compound 17a acetoxy C-norpregn-4ene-3,20-dione (XII).The 17a-acet0xy group may be hydrolyzed to the =17rx-ol XIII withaqueous base and optionally reacylated with propionic or butyricanhydrides and an acid catalyst.

It will be apparent to one skilled in the art of organic chemistry thatthe starting material for the preparation of the inventive compounds maypossess further substituents and/ or double bonds which do not hinderthe conduct of the reactions described herein. Alternatively, suchgroups may be introduced at an appropriate stage in the synthetic routeby'reactions known to the art. Exemplary of such groups are methyl,hydroxy, acyloxy, halo, amino, or a double bond. The 19-methyl group mayalso be eliminated. Insofar as these compounds or their preparation donot depart from the essential aspect of the present invention, i.e.,C-norpregnanes, they are thus considered equivalents of the compoundsspecifically described.

The C-norpregnanes of the present invention are administered to anappropriate subject in the form of tablets or capsules containingeffective, but nontoxic amounts of steroid mixed with a conventionalsolid carrier. The carrier contains one or more standard ingredientssuch as starch, sugar, gums, etc. They are also administered in an oilsolution such as sesame oil. They may further be administered in theform of suppositories, dissolved or suspended in a fatty or waxy vehiclewhich melts approximately at body temperature, or topically in the formof an ointment or cream in which they are dissolved or suspended in anappropriate base.

The following example-s are to be considered illustrative of thecompounds of the invention, but are not to be considered as limiting thescope thereof.

Example 1 To a solution of 5.01 g. of 3a,20B-dihydroxy-5p-pregnan-l2-one (II, US. 2,940,991) in tertbutanol is added 60 ml. of 1.02molar potassium tert-butoxide. The solution is agitated under positiveoxygen pressure for 2 hours at room temperature, and the reactionmixture is concentrated at 25-30 to approximately one-half its originalvolume. The concentrate is diluted with Water and the aqueous solutionis acidified with 4.5% phosphoric acid. The precipitate is extractedwith methylene chloride and the organic phase is extracted with 5%sodium bicarbonate. The residue from evaporation of the dried methylenechloride solution is crystallized from acetone-hexane solution to give3oc,1 1,20,,8-trihydroxy 5,8 pregn-9(11)- en-12-one (III), M.P. 201. Thesodium bicarbonate solution is acidified and the precipitated acidfraction is filtered and recrystallized from methanol-water solution togive 3m,11,20p trihydroxy-Sfl-C-norpregnane-ll-carboxylic acid (IV) as amonohydrate, M.P. 136".

Example 2 A solution of 66 g. of 3a,20p-dihydroxy-Sfi-pregnan- 12-one(II) in 1 liter of tert-butanol is treated with 115.6 g. of potassiumtert-butoxide. The agitated solution is exposed to oxygen under aslightly positive pressure for 27 hours and is then heated at refluxtemperature for 18 hours. The suspended solid is filtered and thefiltrate is concentrated to 450 ml. The concentrate is diluted withwater, acidified with dilute phosphoric acid and the precipitated solidis extracted with ethyl acetate. The filter cake is dissolved in Water,acidified with phosphoric acid and the precipitated solid is extractedwith ethyl acetate. The combined ethyl acetate extracts are washed withsodium bicarbonate solution and the bicarbonate washes are acidifiedwith dilute phosphoric acid. The precipitated 30,11,205-trihydroxy-55-C-norpregnane-1l-carboxylic acid, M.P. 130-3 (IV) iscollected by filtration.

341,1l,20fl-trihydroxy-5,8-pregn-9(11)-en-12-one (III) is converted to30,11,20l3trihydroxy-5fi-C-norpregnane-11- carboxylic acid (IV) byreaction with potassium tertbutoxide in tert-butanol. Thus 0.9 g. of IIIis dissolved in 250 ml. of tert-butanol, 2.0 g. of potassiumtert-butoxide is added, and the turbid reaction mixture is refluxedunder nitrogen overnight. The reaction mixture is concentrated, dilutedwith Water, and acidified, and the precipitated 3a,11,20[3-trihydroxy5,8 C norpregnane-l 1- carboxylic acid (IV) is collected by filtration,M.P. 131-3.

Example 3 A solution of 44 g. of 301,11,208-trihydroxy-5;8-C-norpregnane-ll-carboxylic acid (IV) in 250 ml. ofglacial acetic acid is treated with a suspension of 64 g. of leadtetraacetate in 200 ml. of acetic acid. The addition is carried out withcooling and the reaction is permitted to proceed for 18 hours at roomtemperature. The reaction mixture is diluted with a mixture of 2.5liters of 2.5% aqueous potassium iodide solution and 8-00 ml. ofmethylene chloride. The precipitated salts are filtered and thesolutions partitioned. The organic phases is Washed with 5% sodiumthiosulfate and bicarbonate solutions. The combined and dried methylenechloride extracts are evaporated to a crystalline residue which isrecrystallized from acetone-hexane to give3a,205-dihydroxy-5fi-C-norpregnan-ll-one (V), M.P. 167-168".

Example 4 To a solution prepared by dissolving 3.74 g. of sodium metalin 120 ml. of anhydrous propylene glycol is added 5.5 ml. of anhydroushydrazine and 7.9 g. of solid 3u,20B-dihydroxy-5fl-C-norpregnan-1l-one(V). The mixture is protected from moisture and agitated at gentlereflux temperature for 18 hours. Then the temperature is elevated to180-185 and maintained for 3 hours under azeotropic distillationconditions. The temperature of the reaction mixture is raised to 210 andmaintained for 4 hours. The cooled reactants are permitted to remain atroom temperature overnight and the gelatinous mass is diluted with waterand the crude Sfi-C-norpregnane- 3a,20B-diol is filtered and dried.Recrystallization from benzene gives the pure diol, M.P.'17980.Sfl-C-norpregnane-3u,11,20-triol is obtained by chromatography of theresidue of crystallization. Thus a solution of 2 g. of a mixture of thediol and triol in 350 ml. of benzene is chromatographed on 60 g. ofactivity III Woelm alumina. Elution with benzene gives the diol andelution with a methylene chloride-methanol solution gives the triol,M.P. 184.5

Example 5 A solution of 6.3 g. of 3u,20,8-dihydroxy-Sfl-Onorpregnane in300 ml. of 2:1 acetone: chloroform is cooled to ice-bath temperature anda solution of chromic acid is slowly added to a slight excess. Thereaction mixture is diluted to 2 liters with water and the crude productis recovered by extraction with methylene chloride. The organic phase isWashed with aqueous sodium bicarbonate solution, dried and concentratedto give crude crystalline Sfl-C-norpregnane-3,20-dione (VI),Recrystallization from acetone-hexane solution elevates the M.P. to159-60.

ii Example 6 A solution of 1.4 g. of 5B-C-norpregnane-3,ZO-dione (VI) in15 ml. of dimethylformamide containing 35 mg. of p-toluenesulfonic acidis treated with a solution of 0.748 g. of bromine in 35 ml. ofdimethylformamide over a 3 hour interval. At the end of the addition ofreactants, the reaction is permitted to proceed at 25 for 30 minutes.The reaction solution is diluted with 400 ml. of water and theprecipitated solid is collected by filtration. Recrystallization of thedried precipitate from acetone-hexane solution gives4-bromo-5/i-C-norpregnane-3,20-dione (VII), M.P. -6 dec.

Example 7 A solution of 0.80 g. of 4-bromo-5,6-C-norpregnane-3, 20-dione(VII) in 25 ml. of 1:1 ('v./v.) methylene chlorideztert-butyl alcohol istreated with 0.40 g. of semicarbazide. The mixture is stirred at 25 for1 hour and a solution of 3 ml. of pyruvic acid in 25 ml. of 20% aqueousacetic acid is added. The solution is permitted to remain at 25 for 18hours, then concentrated in vacuo, diluted with water, and theprecipitate extracted into methylene chloride. The organic phase isWashed with sodium bicarbonate solution and dried, and is concentratedto a crystalline residue. The residue aflFords C-norpregn-4ene-3,20-diode (VIII), M.P. 1445,,Ot +261.1, on recrystallization fromacetone-hexane solution.

Example 8 Example 9 A solution of 17 g. of the ketone of Example 8 and 1g. of p-toluenesulfonic acid in 250 ml. of acetic anhydride is distilledslowly through a short column during 5 hours until most of the solventis gone. The residue is poured into ice water and extracted withmethylene chloride. After washing with dilute sodium carbonate solutionand drying, the methylene chloride extracts are evaporated to a residue.The residue is dissolved in benzene-petroleum ether (1:2) and passedthrough a column of 200 g. of activity III Woelm alumina. Evaporation ofthe eluate gives the product 3u,20-diacetoxy-Sfl-C-norpregn-17(20)- ene(IX), which is used directly in the next step.

Example 10 A solution of 18 g. of the diacetate IX of Example 9 in 250ml. of chloroform is treated with 12 g. of m-chloroperbenzoic acid inportions. After 2 hours at room temperature the reaction mixture isWashed with sodium sulfite solution and then with dilute sodiumcarbonate. Drying and evaporation of the methylene chloride phase gives3a,20,B dia-cetoxy-17a,20u-epoxy-5fl-C-norpregnane (X), which is useddirectly in the next step.

Example 11 A solution of 18 g. of the epoxy diacetate X of Example 10 in300 ml. of ethanol is treated with 300 ml. of 5% sodium hydroxide. Theaddition is carried out at room temperature with stirring during 20minutes. After 1 hour, 500 ml. of water is added, the reaction mixtureis cooled and filtered, and the filter cake is recrystallized frommethanol-acetone to give 3a,17a-dihydroXy-Sfi-C-norpregnan- 20-one (XI).

Example 12 A solution of 10 g. of the diol XI of Example 11 in 50 m1. ofacetic anhydride containing 0.2 g. of p-toluenesulfonic acid is stirredat room temperature for 20 hours. The reaction mixture is poured intoice water and extracted With methylene chloride. After washing withsodium hydroxide solution and drying, the methylene chloride phases areevaporated. The residue of 3a,17a-di-.

acetoxy-SB-C-norpregnan-20-one is' used directly in the next step.

Example 13 A solution of 11 g. of the diacetate of Example 12 in 100 ml.of ethanol is treated with a solution of 1.1 g. of sodium hydroxide in20 ml. of Water. The addition is carried out during 1 hour, withstirring at room temperature. After a total reaction time of 3 hours,200 ml. of water is added and the reaction is cooled and filtered. Thefilter cake is recrystallized from acetone-hexane to give3ahydroxy-17a-acetOXy-SB-C-norpregnan-20-one.

Example 14 A stirred solution of 8 g. of 3a-hydroxy-17a-acetoxy-SB-C-norpregnan-ZO-one in 100 ml. of acetone is cooled to C. and treatedwith an excess of chromic acid. After 3 minutes the reaction mixture ispoured into water and extracted with methylene chloride. Evaporation ofthe combined and dried methylene chloride extracts gives 17aacetoxy-8-C-norpregnane-3,20-dione.

Example 15 A solution of 0.93 g. of 4-bromo-17a-acetoxy-5B-C-norpregnane-3,20-dione in 25 ml. of 1:1 (v./v.) methylenechloride:tert-butyl alcohol is treated with 0.40 g. of semicarbazide.The mixture is stirred at 25 for 1 hour and a solution of 3 ml. ofpyruvic acid in 25 ml. of aqueous acetic acid is added. The solution ispermitted to remain at for 18 hours, then concentrated in vacuo, dilutedwith water, and the precipitate extracted with methylene chloride. Theorganic extracts are washed with sodium bicarbonate solution and dried,and concentrated to a residue. The product,17a-acetoxy-C-norpregn-4-ene- 3,20-dione (XII), is recrystallized fromacetone-hexane.

Example 17 A solution of 4.5 g. of 17a-acetoxy-C-norpregn-4-ene-3,20-dione (XII) in 75 ml. of ethanol is treated With 75 ml. of 5%sodium hydroxide. The addition is carried out at room temperature withstirring over 20 minutes. After 1 hour, 125 ml. of water is added, thereaction mixture is cooled and filtered, and the filtered solidrecrystallized to give 17a-hydroxy-C-norpregn-4-ene-3,20-dione (XIII).

Example 18 A solution of 2 g. of 17a-hydroxy-C-norpregn-4-ene-3,20-dione in 20 ml. of propionic anhydride containing 0.05

g. of p-toluenesulfonic acid is allowed to stand at room temperatureovernight. The solution is poured into ice water, allowed to stand, andthe resulting solid filtered oil. Recrystallization gives17a-propionoxy-C-norpregn-4-ene- 3,20-dione. 7

Example 19 A stirred solution of 4 g. of 3a,20/3-dihydroxy-5 3-C-norpregnan-ll-one in ml. of acetone is cooled to 0 C. and treated withan excess of chromic acid. After 3 minutes the reaction mixture ispoured into water and extracted with methylene chloride. Evaporation ofthe dried organic extract gives 5fl-C-norpregnane-3,11,20-trione.

We claim:

1. A compound of the structure wherein:

A is selected from the group consisting of a single bond and a doublebond;

X is selected from the group consisting of =0 and =(H, OH); and

R is selected from the group consisting of hydrogen, hydroxy and loweralkanoyloxy of up to 5 carbon atoms.

2. A compound of the structure oogaxgnanm References Cited FOREIGNPATENTS 1,316,008 12/1962 France.

LORRAINE A. WEINBERGER, Primary Examiner.

V. GARNER, Assistant Examiner.

1. A COMPOUND OF THE STRUCTURE